Evidence for exon shuffling is sensitive to model choice.

Area of Science:

• Evolutionary biology
• Genomics
• Molecular evolution

Background:

• Exon shuffling is a proposed mechanism for protein evolution, suggesting introns facilitate new domain combinations.
• This theory predicts introns are preferentially located near protein domain boundaries.
• Previous studies tested this by comparing intron-domain boundary correspondence against chance positioning.

Purpose of the Study:

• To investigate how the selection of a null model influences the statistical significance of exon shuffling.
• To adapt and apply more realistic null models for genome-wide analyses.
• To evaluate the impact of different null models on assessing exon shuffling across diverse genomes.

Main Methods:

• Extended single-gene null models for genome-wide analyses.
• Applied these models to 21 metazoan and fungal genomes.
• Compared results obtained using a uniform null model versus more realistic null models.

Main Results:

• The uniform null model fails to accurately represent exon lengths and significantly underestimates chance agreement.
• This uniform model overestimates the significance of intron-domain correspondence by up to 100 orders of magnitude.
• Model choice had a more pronounced effect on exon shuffling assessment in fungal genomes compared to metazoan genomes.

Conclusions:

• The uniform null model is overly permissive and may lead to exaggerated conclusions about the role of exon shuffling in multidomain protein evolution.
• Different evolutionary conclusions regarding exon shuffling were reached for seven of the 16 fungal genomes studied based on model choice.
• Genome-wide studies should carefully consider and validate their chosen null models to accurately assess evolutionary mechanisms.